PROJECT SUMMARY Dr. Brust is an infectious diseases specialist and physician-scientist at Albert Einstein College of Medicine. His multidisciplinary patient-oriented research (POR) program focuses on the interplay of tuberculosis (TB) and HIV in South Africa. A K24 Award would allow him to expand his POR program and develop a robust mentoring program in TB, HIV and global health research at Einstein. Worldwide, TB is the most common cause of death in patients with HIV, and the growing epidemic of drug-resistance threatens decades of gains in TB prevention and care. With an emerging pipeline of novel and repurposed TB medications, there is an urgent need for innovative research in TB pharmacology, genomics, and clinical trials to evaluate these drugs. Similarly, there is a need to train the next generation of scientists in multidisciplinary TB/HIV and global health POR. Dr. Brust's research program of clinical, epidemiologic, and translational studies is built upon a network of outstanding collaborators in pharmacology, genomics, microbiology and epidemiology. He has a strong record of successfully mentoring pre-and post-doctoral trainees from multiple institutions and using his collaborators to provide mentees with broad technical and professional expertise. Einstein has a rich environment for training clinical investigators through its medical school, post-doctoral fellowships and multi- disciplinary centers (CTSA, CFAR, Global Health). Within this highly conducive training environment and with a multi-institutional and multinational collaborative research team, Dr. Brust can expand his comprehensive mentoring program at Einstein and internationally. His research program is unique at Einstein and his mentorship is sought by trainees and junior investigators. His mentorship focuses on the design and execution of hypothesis-driven research to assist mentees in becoming independent investigators. By allowing him to decrease his clinical responsibilities, this K24 award will permit him to devote more time to mentorship and to take on a larger number of mentees. The award will also advance his immediate and long-term career goals to: 1) Increase his knowledge of clinical pharmacology to inform current and future studies of new TB medications; 2) Understand how whole genome sequencing can reveal mechanisms of acquired TB resistance; 3) Expand clinical trials skills to facilitate the design and implementation of TB/HIV trials for novel drugs; and 4) Enhance the structure and content of his mentorship of trainees pursuing careers in TB/HIV and global health POR. Finally, this award will support an innovative sub-study of Dr. Brust's new R01 to further investigate the TB drug clofazimine: 1) To develop a novel assay to measure intracellular clofazimine concentrations; 2) To correlate intracellular clofazimine concentrations with the emergence of bedaquiline resistance following a treatment interruption; and 3) to compare intracellular clofazimine concentrations in alveolar macrophages with that in PBMCs. A K24 award will provide vital protected time, enabling Dr. Brust to build upon his current success and giving him the skills to grow as both an investigator and as a mentor.